Inhibitors of macrophage infectivity potentiator-like PPIases affect neisserial and chlamydial pathogenicity

Area of Science:

• Microbiology
• Bacteriology
• Drug Discovery

Background:

• Pathogenic bacteria like Chlamydia trachomatis, Neisseria gonorrhoeae, and Neisseria meningitidis utilize surface-exposed macrophage infectivity potentiator (MIP)-like proteins for pathogenicity.
• MIP proteins possess peptidyl-prolyl isomerase (PPIase) activity, a function known to be inhibited by compounds such as rapamycin and FK506.

Purpose of the Study:

• To investigate pipecolic acid derivatives as potential inhibitors of MIP-like proteins from C. trachomatis and N. gonorrhoeae.
• To evaluate the antimicrobial efficacy of identified MIP inhibitors against key pathogenic bacteria.

Main Methods:

• Screening of pipecolic acid derivatives for inhibitory activity against chlamydial and neisserial MIP.
• Assessing the impact of MIP inhibitors on the developmental cycle of C. trachomatis in HeLa cells.
• Evaluating the effect of MIP deletion or inhibition on the survival of N. gonorrhoeae with neutrophils and N. meningitidis in epithelial cells.

Main Results:

• Two novel MIP inhibitors, PipN3 and PipN4, were identified from pipecolic acid derivatives.
• PipN3 and PipN4 demonstrated significant effects on the developmental cycle of C. trachomatis.
• Inhibition or deletion of MIP impacted the survival of N. gonorrhoeae and N. meningitidis in host cells and immune environments.

Conclusions:

• MIP-like proteins are crucial for the pathogenicity of C. trachomatis, N. gonorrhoeae, and N. meningitidis.
• Pipecolic acid derivatives, specifically PipN3 and PipN4, represent promising antimicrobial agents against these significant bacterial pathogens.